Modulating nerves within bone using bone fasteners

ABSTRACT

Methods of using hardware (e.g., bone screws, anchors or other devices) previously inserted within the body to facilitate energy delivery are disclosed. The energy delivery (e.g., thermal energy) may be used for neuromodulation (such as stimulation or denervation), tissue heating and ablation, curing, and other applications in the spine and non-spine orthopedic locations.

FIELD

Various embodiments of the invention pertain generally to modulating nerves within bone (e.g., intraosseous nerves) using pre-existing hardware (e.g., implants, screws), and more particularly to modulation of basivertebral nerves within vertebral bodies of the spine.

BACKGROUND

Back pain is a very common health problem worldwide and is a major cause for work-related disability benefits and compensation. Back pain may arise from strained muscles, ligaments, or tendons in the back and/or structural problems with bones or spinal discs. The back pain may be acute or chronic. Treatments for chronic back pain vary widely and include physical therapy and exercise, chiropractic treatments, rest, pharmacological therapy such as pain relievers or anti-inflammatory medications, and surgical intervention such as vertebral fusion, discectomy or disc repair. Existing treatments can be costly, addictive, temporary, ineffective, and/or can increase the pain or require long recovery times.

SUMMARY

Several embodiments of the invention are directed to the use of pre-existing implants in the body to facilitate energy delivery. The energy delivery (e.g., radiofrequency energy or other thermal energy) is used for neuromodulation (such as stimulation or denervation), tissue heating and ablation (including tumor ablation), curing, and other applications in the spine and non-spine orthopedic locations. Energy delivery to non-orthopedic locations is also contemplated herein. In addition to the use of pre-existing implants, temporary instruments placed in the body may also facilitate energy delivery according to several embodiments disclosed herein.

Implants or other hardware used as conductive devices according to embodiments described herein include, but are not limited to, bone screws, bone anchors, fastening devices, fusion devices, cages, nails, support plates, and other devices that possess conductive properties. Applications include, but are not limited to, the spine, knee, shoulder, hip, cranial bone, and small joints.

In several embodiments of the invention, pedicle screws or other implants or devices having at least a portion located within a vertebral body or other target bone can be used to deliver energy or agents to modulate nerves within the vertebral body or other target bone locations.

The terms “modulation” or “neuromodulation”, as used herein, shall be given their ordinary meaning and shall also include ablation, permanent denervation, temporary denervation, disruption, blocking, inhibition, therapeutic stimulation, diagnostic stimulation, inhibition, necrosis, desensitization, or other effect on tissue. Neuromodulation shall refer to modulation of a nerve (structurally and/or functionally) and/or neurotransmission. Modulation is not limited to nerves and may include effects on other tissue.

Several embodiments of the invention have one or more of the following advantages as compared to direct application of energy (i) more diffuse, but controlled, heating can occur, (ii) energy is not applied directly to tissue (which may be beneficial when direct contact of an electrode to tissue is not desired), (iii) energy can be delivered to a tortuous (e.g., curved) and/or remote area where direct access to an electrode or other energy source may not be desirable), and (iv) because a pre-existing implant is used, an additional incision or pathway need not be created.

In some embodiments, one or more sensors are provided to detect the amount of energy delivered to the target and/or temperature of the target tissue. The sensors may include transducers, thermocouples, thermistors, and/or the like.

In several embodiments, specific bone screws having specialized conductive and/or insulating elements are used. For example, bone screws having insulating elements along the length except for a distal end portion or tip such that only the distal end portion or tip of the bone screw delivers heat or energy to the bone are used, thereby providing controlled delivery of energy to the bone. However, in many embodiments, the pre-existing implant (with no special adaptations) is used.

In some embodiments, the pre-existing implant (e.g., a bone screw) may be used as a guide to align and facilitate navigation of an independent energy delivery device.

In some embodiments, a bone screw or other anchor or fastening member is a primary means of conducting heat to nerves within bone without any intervening structures or other implantable devices (e.g., implantable stimulators). In some embodiments, one or more electrodes are placed in contact with one or more pre-existing implants (e.g., bone screws or other extant hardware) to effect neuromodulation (e.g., through heat, or thermal energy) instead of the electrodes directly contacting the tissue to be heated or stimulated. In some embodiments, energy is applied to the pre-existing implants during a single procedure and not as series of procedures repeated over a duration of time; however, in some embodiments, energy may be applied on more than one occasion.

In accordance with several embodiments, a method of treating back pain of a subject comprises performing a spinal fusion procedure between two adjacent vertebral bodies. The method may comprise inserting a distal end of a first pedicle screw within a cancellous bone region of a first vertebral body; and applying thermal energy to the first pedicle screw to conduct heat to the cancellous bone region sufficient to modulate a nerve within the cancellous bone region of the first vertebral body. In one embodiment, the method comprises inserting a distal end of a second pedicle screw within the cancellous bone region of the first vertebral body and applying thermal energy to the second pedicle screw to conduct heat to the cancellous bone region of the first vertebral body sufficient to modulate the nerve within the cancellous bone region of the first vertebral body in combination with the applied thermal energy to the first pedicle screw. In one embodiment, the method comprises inserting a distal end of a distal end of a pedicle screw (either a second pedicle screw or a third pedicle screw) within the cancellous bone region of a second vertebral body and applying thermal energy to the pedicle screw to conduct heat to the cancellous bone region of the second vertebral body sufficient to modulate a nerve within the cancellous bone region of the second vertebral body. The thermal energy may be applied to the various pedicle screws successively or simultaneously, or a combination of both (e.g., two at a time).

In accordance with several embodiments, a method of applying energy to the body comprises identifying a pre-existing implant proximate a region of interest. In one embodiment, the pre-existing implant comprises a conductive material. The region of interest may comprise a nerve within or proximate a bone. In one embodiment, the method comprises applying thermal energy to the pre-existing implant to conduct heat to the region of interest sufficient to modulate the nerve within or proximate the bone. For example, the bone may be a vertebral body and the nerve may be a basivertebral nerve within the vertebral body. The bone may alternatively be a bone of the shoulder, hip, cranium, wrist, arm, hand, knee, elbow, small joints, or other bone. In one embodiment, the region of interest is within a cancellous bone portion. In one embodiment, the region of interest is within or proximate a periosteal or osteal potion of the bone. The thermal energy may be applied using a radiofrequency energy delivery device coupled to and powered by a radiofrequency generator or other energy source. The energy delivery device may comprise one or more electrodes to deliver the thermal energy. The electrodes may be coupled to the energy source via one or more electrical wires or leads.

In accordance with several embodiments, a method of treating back pain in a subject having a pedicle screw inserted within a cancellous bone region of a vertebral body comprises identifying a pedicle screw proximate a region of interest. The pedicle screw may comprise a conductive material. At least a portion of the pedicle screw may be in contact with a cancellous bone region and the region of interest may comprise a nerve within the cancellous bone region. In one embodiment, the method comprises applying thermal energy to the pedicle screw to conduct heat to the cancellous bone of the vertebral body sufficient to modulate the nerve within the cancellous bone region. In one embodiment, the temperature of the thermal energy is between about 75 degrees Celsius and about 100 degrees Celsius. The thermal energy may be applied for a period of about 10 seconds to about 30 minutes (e.g., 10 seconds to 30 seconds, 20 seconds to 60 seconds, 30 seconds to 2 minutes, 1 minute to 5 minutes, 5 minutes to 15 minutes, 10 minutes to 30 minutes, 15 minutes to 30 minutes, or overlapping ranges thereof). In one embodiment, the applied thermal energy is sufficient to denervate the nerve. In one embodiment, the applied thermal energy is sufficient to ablate the nerve to permanently treat back pain associated with the nerve. The thermal energy may be applied using a heat source, such as a radio-frequency generator.

The methods summarized above and set forth in further detail below describe certain actions taken by a practitioner; however, it should be understood that they can also include the instruction of those actions by another party. Thus, actions such as “For example, actions such as “applying thermal energy” include “instructing the applying of thermal energy.” Further aspects of embodiments of the invention will be discussed in the following portions of the specification. With respect to the drawings, elements from one figure may be combined with elements from the other figures.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the invention will be more fully understood by reference to the following drawings which are for illustrative purposes only:

FIG. 1 illustrates a pedicle screw system connected to a portion of a human spine.

FIG. 2 illustrates pedicle screws inserted within a vertebral body of the spine and application of thermal energy to the pedicle screws.

DETAILED DESCRIPTION

Several embodiments of the invention are directed to systems and methods for modulating one or more nerves within bone using a previously inserted implant (such as a bone fastener or anchor member or other hardware that is already extant). In some embodiments, an intraosseous nerve within a vertebral body of the spine is modulated using one or more fasteners (e.g., pedicle screws) previously inserted within the vertebral body. For example, heat or thermal energy can be applied to a pedicle screw (e.g., using a heat source) and thermal energy may be conducted by heat transfer to one or more intraosseous nerves (e.g., a basivertebral nerve believed to be contributing to back pain) within the cancellous bone region of the vertebral body.

In accordance with several embodiments of the inventions, nerve modulation is performed in combination with, or in conjunction with, spinal fusion or spinal stabilization to treat back pain. The neuromodulation may be performed contemporaneously with the spinal fusion or during a separate treatment procedure. Although the systems and methods described herein are primarily directed to modulation of a basivertebral nerve of a vertebral member, the treatment may be applied to any nerve and/or to any tissue segment of the body (e.g., tumors or tissue growths within bone).

FIG. 1 illustrates a pedicle screw assembly 100 connected to a portion of a human spine 102. For example, the pedicle screw assembly 100 may be connected to the spine 102 during a spinal fusion or spinal stabilization procedure. The pedicle screw assembly 100 comprises multiple pedicle screws 104, multiple interconnected rods 106 and multiple plates or members 108. In some embodiments, the pedicle screws 104 are inserted through a pedicle or other bony portion of the spine 102 and into an inner cancellous bone region of a vertebral body 110. The pedicle screw assembly 100 may be used to stabilize a portion of the spine (e.g., one or more spine segments or levels) or to repair spinal defects (e.g., scoliosis, herniated discs, fractures, etc.). During a spinal fusion or stabilization procedure, fusion or graft material may be inserted between adjacent vertebral bodies and/or various portions of the spine (e.g., intervertebral disc, facets, spinous process) may be removed. For example, a fusion may be performed or may have been performed of the L5 and S1 vertebrae. The pedicle screw assembly 100 represents an embodiment of pre-existing hardware that could be used; other types of hardware could be used in other embodiments.

FIG. 2 illustrates two pedicle screws 204 inserted within a vertebral body 210 of a human spine 202. A distal end of each of the pedicle screws 204 is located within an inner cancellous bone region 215 of the vertebral body 210. As shown in FIG. 2, a portion of a basivertebral nerve 220 may be located within the inner cancellous bone region 215 of the vertebral body 210. In several embodiments, the pedicle screws 204 comprise conductive material that is capable of conducting thermal energy (e.g., transferring heat) to the cancellous bone surrounding the pedicle screw, thereby heating the cancellous bone and at least a portion of the basivertebral nerve 220 located within the cancellous bone. For example, the conductive material may comprise one or more metals or alloys (e.g., copper, silver, gold, titanium, aluminum, brass, stainless steel) and/or conductive polymers (e.g., conductive silicone) or other conductive materials. The pedicle screws may be self-tapping screws.

In accordance with several embodiments of the invention, thermal energy may be applied to one or more pedicle screws (e.g., by an RF energy delivery instrument coupled to an RF generator). The thermal energy may be conducted by heat transfer to the surrounding cancellous bone, thereby heating up the cancellous bone. In accordance with several embodiments, the thermal energy is applied with a sufficient temperature and over a sufficient duration of time to heat the cancellous bone such that the basivertebral nerve extending through the cancellous bone of the vertebral body is modulated. In several embodiments, modulation comprises permanent ablation or denervation. In some embodiments, modulation comprises temporary denervation or inhibition. In some embodiments, modulation comprises stimulation. In some embodiments, thermal energy is applied to only one pedicle screw. In some embodiments, thermal energy is applied to multiple pedicle screws, either simultaneously or successively. In some embodiments, multiple levels of vertebral bodies are treated simultaneously or successively by application of thermal energy to pedicle screws or other bone fasteners. In one embodiment, a bipolar system is used to connect a first (e.g., active) electrode to a first pedicle screw and to connect a second (e.g., return) electrode to a second pedicle screw (e.g., to create an electrically conductive pathway between the first electrode and the second electrode). In one embodiment, a first alligator clip can be connected to a first pedicle screw and a second alligator clip can be connected to a second pedicle screw. The first pedicle screw may be on a first side of a vertebral body and the second pedicle screw may be on a second side of the vertebral body, with the first and second sides being defined by any path (e.g., line) extending through a general midpoint of the vertebral body. In one embodiment, the first and second sides are on opposite sides of a line substantially aligned with a spinous process connected to the vertebral body.

Thermal energy may be applied by a thermal energy delivery device 230 (e.g., a heating instrument, an electric or gas-fired iron similar to a soldering iron, a monopolar or bipolar electrode probe, etc.) Any energy delivery device capable of delivering energy can be used (e.g., RF energy delivery devices, microwave energy delivery devices, laser devices, infrared energy devices, other electromagnetic energy delivery devices, ultrasound energy delivery devices, and the like). In some embodiments, multiple energy delivery devices 230, 230′ may optionally be used simultaneously at different locations (e.g., in conjunction with different bone fasteners at a single spine level or at different spine levels). In some embodiments, a single energy delivery device may have multiple members, branches, or extensions configured to apply energy at different locations. For example, a single energy delivery device may comprise a plurality of energy delivery members, such as multiple electrodes (either on a single continuous structure or on separate extensions or branches). The branches or extensions may be separately steerable or controllable (e.g., using pull wire, shape memory material, and/or active steering mechanisms). Pre-existing devices or implants within the vertebral body or other bone capable of conducting heat other than pedicle screws may also be used to conduct heat to bone tissue to modulate intraosseous nerves, such as staples, bone anchors or non-threaded bone fasteners.

Temperatures of the thermal energy applied to the pedicle screw or other bone fastener may range from about 70 to about 115 degrees Celsius (e.g., from about 70 to about 90 degrees Celsius, from about 75 to about 90 degrees Celsius, from about 80 to about 100 degrees Celsius, from about 85 to about 95 degrees Celsius, from about 90 to about 110 degrees Celsius, from about 95 to about 115 degrees Celsius, or overlapping ranges thereof). The time of treatment may range from about 10 seconds to about 1 hour (e.g., from 10 seconds to 1 minute, 1 minute to 5 minutes, from 5 minutes to 10 minutes, from 10 minutes to 20 minutes, from 15 minutes to 30 minutes, from 20 minutes to 40 minutes, from 30 minutes to 1 hour, from 45 minutes to 1 hour, or overlapping ranges thereof). Pulsed energy may be delivered according to several embodiments herein.

In some embodiments, a heating zone is established and controlled within a vertebral body so as not to heat any portion of the vertebral body within 1 cm of the posterior wall of the vertebral body. For example, a bone screw may include or be provided with insulating elements extending along the length from the exposed proximal end to the distal end with the distal end or tip being uninsulated, such that heat or energy is delivered to the vertebral body in a controlled manner. In some embodiments, the heating zone is maintained to a region that is between about 10% and about 80%, between about 5% and about 70%, between about 10% and about 65%, between about 20% and about 60%, between about 30% and about 55%, or overlapping ranges thereof, of the distance from the posterior wall to the anterior wall of the vertebral body. In one embodiment, the heating zone is configured to encompass a terminus of a basivertebral nerve.

Cooling may be provided to prevent surrounding tissues from being heated during the nerve modulation procedure. Cooling may be applied by circulating fluid through one or more lumens of an energy delivery device. The cooling may be provided by convective cooling or conductive cooling. The circulating fluid may be provided by a fluid source (e.g., reservoir) in fluid communication with the energy delivery device. Cooling may be provided by the same instrument used to deliver thermal energy (e.g., heat) to the pedicle screw or a separate instrument.

In some embodiments, cooling may be applied to the pedicle screw or other fastener for nerve modulation instead of heat (e.g., for cryotherapy applications). The temperature and duration of the cooling may be sufficient to modulate intraosseous nerves (e.g., ablation due to excessive cooling). Cooling may be provided by the same instrument used to deliver thermal energy (e.g., heat) to the pedicle screw or a separate instrument.

In some embodiments, a channel may be formed through the pedicle screw for delivery of one or more fluids or agents to the cancellous bone region. The channel may be formed by a device configured to bore through, drill through or puncture the pedicle screw. The agents delivered to the bone region may comprise bone morphogenetic proteins, for example. In some embodiments, the fluids or agents delivered to the bone region may comprise chemicals for modulating nerves (e.g., chemoablative agents, nerve-inhibiting agents, or nerve stimulating agents). In some embodiments, the bone screws or fasteners include a channel or lumen into which a heat or energy delivery probe or device may be inserted and advanced in order to deliver controlled heat or energy to the bone. In some embodiments, the bone screws or fasteners are fenestrated. For example, the bone screws or fasteners may have one or more holes or openings along at least a portion of the length of the bone screws or fasteners (e.g., for delivering liquid, gas, or solid materials to a target location).

In some embodiments, tumors or bone metastases within the vertebral body or other bones in which the pedicle screw is inserted may be targeted by delivering thermal energy via the pedicle screw or by delivering therapeutic agents (e.g., chemotherapy agents) through a channel or lumen formed or previously existing in the pedicle screw or other bone fastener. In some embodiments, the thermal energy is delivered using the pedicle screw and the therapeutic agents are delivered without use of the pedicle screw.

In some embodiments, fractures within the bone surrounding the pedicle screws or other bone fasteners may be treated by applying heat or energy or delivering agents or bone filler material to the bone. For example, bone morphogenetic proteins and/or bone cement may be delivered in conjunction with vertebroplasty or other procedures to treat fractures or promote bone growth or bone healing. In some embodiments, the energy is applied using the pedicle screw and the agents and/or bone filler material is delivered using standard delivery instruments (with or without use of the pedicle screw). In some embodiments, vertebral compression fractures (which may be caused by osteoporosis or cancer) are treated in conjunction with energy delivery using the pedicle screw to modulate nerves to treat back pain.

In some embodiments, nerve modulation is performed in conjunction with (e.g., contemporaneous with) spinal fusion or other spinal stabilization procedures. A stabilization assembly including pedicle screws or other bone fasteners may be affixed or connected to a portion of the spine and then thermal energy may be applied to one or more of the pedicle screws to heat up the inner cancellous bone region sufficient to modulate the nerves. The methods may be performed on thoracic, lumbar, cervical or sacral vertebrae, or a combination thereof. The methods may be performed on vertebral levels or segments that are difficult to access via a percutaneous approach. In one embodiment, a fusion procedure may have been performed to fuse the L5 and S1 vertebrae. Nerve modulation may be performed contemporaneously or post-facto using one or more pedicle screws or other bone fasteners implanted or otherwise inserted within one or more vertebral bodies.

In accordance with several embodiments, the methods of facilitating neuromodulation of intraosseous nerves described herein are performed without requiring knowledge of the exact location of the intraosseous nerve and without forming additional channels or passageways or incisions in bone to access the intraossoeus nerve. For example, the methods described herein do not require any particular approach or curved instruments to be used to facilitate neuromodulation. The methods described herein facilitate neuromodulation with devices previously existing within the bone (e.g., hardware inserted during previous procedures).

In accordance with several embodiments, the systems and methods of treating back pain or facilitating neuromodulation of intraosseous nerves described herein can be performed without surgical resection, without general anesthesia, and/or with virtually no blood loss. In some embodiments, the systems and methods of treating back pain or facilitating neuromodulation of intraosseous nerves described herein facilitate easy retreat if necessary. In accordance with several embodiments of the invention, successful treatment can be performed in challenging or difficult-to-access locations and access can be varied depending on bone structure. One or more of these advantages also apply to treatment of tissue outside of the spine (e.g., other orthopedic applications or other tissue).

While the embodiments are susceptible to various modifications, and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, that the invention is not to be limited to the particular forms or methods disclosed, but to the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the various embodiments described and the appended claims. Any methods disclosed herein need not be performed in the order recited. The methods disclosed herein include certain actions taken by a practitioner; however, they can also include any third-party instruction of those actions, either expressly or by implication. For example, actions such as “applying thermal energy” include “instructing the applying of thermal energy.”

Various embodiments of the invention have been presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. The ranges disclosed herein encompass any and all overlap, sub-ranges, and combinations thereof, as well as individual numerical values within that range. For example, description of a range such as from 70 to 115 degrees should be considered to have specifically disclosed subranges such as from 70 to 80 degrees, from 70 to 100 degrees, from 70 to 110 degrees, from 80 to 100 degrees etc., as well as individual numbers within that range, for example, 70, 80, 90, 95, 100, 70.5, 90.5 and any whole and partial increments therebetween. Language such as “up to,” “at least,” “greater than,” “less than,” “between,” and the like includes the number recited. Numbers preceded by a term such as “about” or “approximately” include the recited numbers. For example, “about 10%” includes “10%.” For example, the terms “approximately”, “about”, and “substantially” as used herein represent an amount close to the stated amount that still performs a desired function or achieves a desired result. 

What is claimed is:
 1. A method of treating back pain in a subject having a pedicle screw inserted within a cancellous bone region of a vertebral body, the method comprising: identifying a pedicle screw proximate a region of interest, wherein the pedicle screw comprises a conductive material, wherein at least a portion of the pedicle screw is in contact with a cancellous bone region, wherein said region of interest comprises a nerve within the cancellous bone region, applying thermal energy to the pedicle screw to conduct heat to the cancellous bone of the vertebral body sufficient to modulate the nerve within the cancellous bone region.
 2. The method of claim 1, wherein the temperature of the thermal energy is between about 75 degrees Celsius and about 100 degrees Celsius.
 3. The method of claim 1, wherein the thermal energy is applied for a period of about 10 to about 30 minutes.
 4. The method of claim 1, wherein the applied thermal energy is sufficient to denervate the nerve.
 5. The method of claim 1, wherein the applied thermal energy is sufficient to ablate the nerve to permanently treat back pain associated with the nerve.
 6. The method of claim 1, wherein the thermal energy is applied using a heat source.
 7. The method of claim 1, wherein the thermal energy is applied using a radio-frequency generator.
 8. A method of treating back pain of a subject, the method comprising: performing a spinal fusion procedure between two adjacent vertebral bodies; inserting a distal end of a first pedicle screw within a cancellous bone region of a first vertebral body; and applying thermal energy to the first pedicle screw to conduct heat to the cancellous bone region sufficient to modulate a nerve within the cancellous bone region of the first vertebral body.
 9. The method of claim 8, further comprising inserting a distal end of a second pedicle screw within the cancellous bone region of the first vertebral body and applying thermal energy to the second pedicle screw to conduct heat to the cancellous bone region of the first vertebral body sufficient to modulate the nerve within the cancellous bone region of the first vertebral body in combination with the applied thermal energy to the first pedicle screw.
 10. The method of claim 9, wherein the thermal energy is applied to the first pedicle screw and the second pedicle screw simultaneously.
 11. The method of claim 8, further comprising inserting a distal end of a second pedicle screw within the cancellous bone region of a second vertebral body and applying thermal energy to the second pedicle screw to conduct heat to the cancellous bone region of the second vertebral body sufficient to modulate a nerve within the cancellous bone region of the second vertebral body.
 12. The method of claim 11, wherein the thermal energy is applied to the first pedicle screw and the second pedicle screw simultaneously.
 13. The method of claim 11, wherein the thermal energy is applied to the first pedicle screw and the second pedicle screw successively.
 14. A method of applying energy to the body, the method comprising: identifying a pre-existing implant proximate a region of interest, wherein the pre-existing implant comprises a conductive material, wherein said region of interest comprises a nerve within or proximate a bone; and applying thermal energy to the pre-existing implant to conduct heat to the region of interest sufficient to modulate the nerve within or proximate the bone.
 15. The method of claim 14, wherein the bone is a vertebral body and wherein the nerve is a basivertebral nerve.
 16. The method of claim 14, wherein the bone is a portion of bone of any of the following: shoulder, hip, cranium, wrist, arm, hand, knee, elbow or small joints.
 17. The method of claim 14, wherein the region of interest is within a cancellous bone portion.
 18. The method of claim 14, wherein the region of interest is within or proximate a periosteal or osteal potion of the bone.
 19. The method of claim 14, wherein the thermal energy is applied using a radiofrequency generator.
 20. The method of claim 14, wherein the thermal energy is applied using at least one electrode. 